Cyclodextrins (CDs) are a class of non-toxic, water-soluble D-glucose based macrocycles with a hydrophobic cavity. CDs typically vary by the number of glucose units. Common members include α-CD (6 glucose units), β-CD (7 glucose units) and γ-CD (8 glucose units), with increasing cavity size. The varying cavity sizes offer increased utility in a wide variety of applications, particularly in drug delivery models. For example, CDs can be used to form “inclusion complexes” in which a drug is included and carried within the cavity. This can be used as a pharmaceutical excipient to improve drug water solubility, chemical stability, and removal of certain drug side effects (such as undesirable taste). CDs have also drawn interest in the cosmetic and food additives industries, in the design of artificial enzymes, gene delivery vehicles, sensors and novel supramolecular assemblies.
CDs can be native or chemically modified on either or both of their primary and/or secondary faces. Typically, an inclusion complex often has lower water solubility than native CDs. Chemical modifications of CDs can change their physico-chemical properties. For example, adding a tosyl group on the primary face of the β-CD renders the molecule near insoluble at room temperature, while adding methyl groups at OH-6 and OH-2 positions significantly increases water solubility. The toxicity of the molecule can also be changed. Therefore, modification of the CD molecule may present certain advantages. However, chemical modification of CDs is typically difficult to achieve, often leading to the formation of a mixture of products that are difficult to separate.
The groups added to the primary or second face can be neutral or charged. For example, Captisol® is an excipient for use with a number of drugs. It is a polyanionic mixture of β-CD derivative having from 1 to 10 sodium sulfobutyl ether groups directly attached via oxygen atoms of the D-glucose thereto (U.S. Pat. No. 5,134,127 (Stella et al)). Capitsol is prepared by reacting a β-CD with 1,4-butyl sultone and sodium hydroxide in water. The obtained product is a mixture containing many positional and regioisomers with varying degrees of substitution at different oxygen positions on the CD, such as substitution at O-2, O-3 and O-6 on the CD. (Luna, et al., Carbohydr. Res., 299, 103-110, 1997; Luna, et al., Carbohydr. Res., 299, 111-118, 1997; Rogmann et al., Carbohydr. Res., 327, 275-285, 2000; http://www.captisol.com/faq/solution-and-solid-state-characteristics-in-captisol).
There are certain disadvantages with Captisol. As it comprises a mixture of compounds, thus resulting in varied compositions, it is difficult if not impossible to define and characterize the product compositions.
Another polyanionic CD compound currently on the market is Sugammadex (by Merck), which is a polyanionic agent obtained from γ-CD. Sugammadex blocks the activity of neuromuscular agents (Yan, et al., Drugs, 2009: 69, 919-42; Calderón-Acedos, et al. Eur. J. Hosp. Pharm. 2012: 19, 248). See also U.S. Pat. No. 6,670,340 (Zhang et al.) and U.S. Pat. No. 6,949,527 (Zhang et al.).
Non-ionic CD-based compounds are also known in the art. One example includes hydroxypropyl-beta CD (HPBCD). However, this exists in a mixture of compounds, similarly resulting in varied compositions.
There is a need for pure anionic or non-ionic CD derivatives for various applications in the pharmaceutical industry, such as those described herein, for example.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.